Stereoselective formation

Several cortisone derivatives with glucocorticoid effects are most active, if they contain fluorine in the 9or-position together with an Il(9-OH group. Both substituents are introduced by the cleavage of a 9,11 -epoxide with hydrogen fluoride. The regio- and stereoselective formation of the -epoxide is achieved by bromohydrination of a 9,11-double bond and subsequent alkali treatment (J. Fried, 1954). 

The Pd-catalyzed hydrogenolysis of vinyloxiranes with formate affords homoallyl alcohols, rather than allylic alcohols regioselectively. The reaction is stereospecific and proceeds by inversion of the stereochemistry of the C—O bond[394,395]. The stereochemistry of the products is controlled by the geometry of the alkene group in vinyloxiranes. The stereoselective formation of stereoisomers of the syn hydroxy group in 630 and the ami in 632 from the ( )-epoxide 629 and the (Z)-epoxide 631 respectively is an example. 

Reduction of isoindoles with dissolving metals or catalytically occurs in the pyrrole ring. Reduction of indolizine with hydrogen and a platinum catalyst gives an octahydro derivative. With a palladium catalyst in neutral solution, reduction occurs in the pyridine ring but in the presence of acid, reduction occurs in the five-membered ring (Scheme 38). Reductive metallation of 1,3-diphenylisobenzofuran results in stereoselective formation of the cw-1,3-dihydro derivative (Scheme 39) (80JOC3982). 

The coupling reaction between lithium dimethylcuprate and acyclic enol phosphates must be carried out between -47 and -98 C for stereoselective formation of g-methyl-a,g-unsaturated esters. 

The addition of methylmagnesium iodide to 2-phenylpropanal is stereoselective in producing twice as much syn-3-phenyl-2-butanol as the anti isomer (entry 5). The stereoselective formation of a particular configuration at a new stereogenic center in a reaction of a chiral reactant is called asymmetric induction. This particular case is one in which the stereochemistry can be predicted on the basis of an empirical correlation called Cram s rule. The structural and mechanistic basis of Cramls rule will be discussed in Chapter 3. 

Treatment of an epimeric mixture of 4-substituted 2-(trimethylsilyloxy)-5-phenyl-3-phenylthio-l,4-oxazine 264 with ZnBr2 led to the stereoselective formation of perhydropyrido[2,l-c][l,4]oxazine 266 via the iminium ion 265 by the phenyl bearing stereocenter directed addition of the olefinic double bond from the /S-face of the cyclic moiety (97SL799, 98T10309). Similarly, an epimeric mixture of (45,9aS)-l-trimethylsilyloxy-4-phenyl-3,4,6,7-tetra-hydropyrido[2,l-c][l,4]oxazine was prepared by cyclization of (Z)-5(S)-phenyl-3-phenvlsulfanyl-2-trimethylsilyloxy-4-[4-(trimethylsilyl)but-3-enyll morpholine (OOSC2565). 

This was ihe first investigation of stereoselective formation of geometric isomers of tertiary amines. The authors suggested most enamine systems should be subject to considerable stereochemical control. 

In a catalytic asymmetric reaction, a small amount of an enantio-merically pure catalyst, either an enzyme or a synthetic, soluble transition metal complex, is used to produce large quantities of an optically active compound from a precursor that may be chiral or achiral. In recent years, synthetic chemists have developed numerous catalytic asymmetric reaction processes that transform prochiral substrates into chiral products with impressive margins of enantio-selectivity, feats that were once the exclusive domain of enzymes.56 These developments have had an enormous impact on academic and industrial organic synthesis. In the pharmaceutical industry, where there is a great emphasis on the production of enantiomeri-cally pure compounds, effective catalytic asymmetric reactions are particularly valuable because one molecule of an enantiomerically pure catalyst can, in principle, direct the stereoselective formation of millions of chiral product molecules. Such reactions are thus highly productive and economical, and, when applicable, they make the wasteful practice of racemate resolution obsolete. 

In 1997, Lindstrom and Somfai reported aza-[3,3]-Claisen enolate rearrangements of vinylaziridines (Scheme 2.45) [70]. Treatment of l-acyl-2-vinylaziridines 179 with LHMDS resulted in the stereoselective formation of seven-membered lactams 181, presumably through a boat-like transition state 180. 

In order to test whether this high level of diastereoselectivity is due to the stereoselective formation of 35 A, or a consequence of rapid equilibration between 35 A and 35 B, both reagents were selectively prepared via the tributylstannanes 38. Treatment of either reagent with chloro-trimethylsilane led to a similar ratio of the diastereomers 36 A/36B, with the anti-diastereomer 36A predominant in both reactions. 

Highly stereoselective formation of. syn-adducts (syn/anti. >95 < 5) results from the titanium(IV) chloride induced addition ofa-unsubsliluled enolsilanes, as well as of the a-dimethyl silylketene acetal, to 2-benzyloxypropanal3. 

Considerable efforts have been devoted to the stereoselective introduction of a /(-methyl function in intermediates for the synthesis of 1 jS-methylcarbapenems. While the trimethylsilyl trifluoromethanesulfonate catalyzed reaction of a 4-acetoxyazetidinone derivative with ketene acetals shows no selectivity, ketene thioacetals lead to stereoselective formation of the a-methyl isomer108. The zirconium enolate, however, shows high /(-methyl selectivity. 

A further improvement utilizes the compatibility of hindered lithium dialkylamides with TMSC1 at —78 °C. Deprotonation of ketones and esters with lithium dialkylamides in the presence of TMSC1 leads to enhanced selectivity (3) for the kinetically generated enolate. Lithium t-octyl-t-butyl-amide (4) appears to be superior to LDA for the regioselective generation of enolates and in the stereoselective formation of (E) enolates. 

An example of a surprisingly facile and stereoselective formation of an eight-membered lactone from an acyclic precursor diene ester was observed during the total synthesis of the antitumor agent octalactin A (148) (Scheme 27) [81]. The dense substitution pattern in cyclization substrate 146 presumably imposes... 

The utility of lOOC reactions in the synthesis of fused rings containing a bridgehead N atom such as pyrrolizidines, indolizidines, and quinolizidines which occur widely in a number of alkaloids has been demonstrated [64]. Substrates 242 a-d, that possess properly positioned aldoxime and alkene functions, were prepared from proline or pipecolinic acid 240 (Eq. 27). Esterification of 240 and introduction of unsaturation on N by AT-alkylation produced 241 which was followed by conversion of the carbethoxy function to an aldoxime 242. lOOC reaction of 242 led to stereoselective formation of various tricyclic systems 243. This versatile method thus allows attachment of various unsaturated side chains that can serve for generation of functionalized five- or six-membered (possibly even larger) rings. 

Complex (XV), which isomerizes to (XVI) in a subsequent, slower step, almost certainly is the kinetic product. Its stereoselective formation from... 

To date, direct asymmetric synthesis of optically active chiral-at-metal complexes, which by definition leads to a mixture of enantiomers in unequal amounts thanks to an external chiral auxiUary, has never been achieved. The most studied strategy is currently indirect asymmetric synthesis, which involves (i) the stereoselective formation of the chiral-at-metal complex thanks to a chiral inductor located either on the ligand or on the counterion and then (ii) removal of this internal chiral auxiliary (Fig. 4). Indeed, when the isomerization of the stereogenic metal center is possible in solution, in-... 

Sutherland JB, JP Freeman, AL Selby, PP Fu, DW Miller CE Cerniglia (1990) Stereoselective formation of a K-region dihydrodiol from phenanthrene by Streptomyces flavovirens. Arch Microbiol 154 260-266. 

Finally, the most significant mechanistic feature of the Ramberg-Backlund rearrangement is the stereoselective formation of ds-olefin products, as a result of the preferential cis-positioning of the pair of R groups in the episulfone-forming transition state, variously attributed to London forces , to diastereoselectivity in carbanion formation and to steric attraction . However, with the use of stronger bases such as potassium t-butoxide °, the trans-olefin predominates (equation 52), apparently due to prior epimerization of the kinetically favoured cts-episulfone, and subsequent loss of the sulfur dioxide. Similarly, when the episulfone intermediates possess unusually acidic... 

A similar preference for formation of the syn aldol is found for other Z-enolates derived from ketones in which one of the carbonyl substituents is bulky. Ketone enolates with less bulky substituents show a decreasing stereoselectivity in the order r-butyl > i-propyl > ethyl.2c This trend parallels a decreasing preference for stereoselective formation of the Z-enolate. 

Entry 6 shows a stereoselective formation of a highly substituted frans-decalin system. The reaction in Entry 7 establishes a taxanelike structure. The stereochemistry is consistent with a TS in which both the carbonyl oxygen and the methoxy group are coordinated to aluminum. 

An example of this type is the highly stereoselective formation of lanosterol (0-6) from (S)-2,3-oxidosqualene (0-5) in Nature, which seems not to follow a concerted mechanism (Scheme 0.2) [9],... 

As shown earlier in many examples, the Claisen rearrangement of allyl vinyl ethers also provides a very powerful method for carbon-carbon bond formation in domino processes. Usually, the necessary ethers are formed in a separate step. However, both steps can be combined in a novel domino reaction developed by Buchwald and Nordmann [306]. This starts from an allylic alcohol 6/4-102 and a vinyl iodide 6/4-103, using copper iodide in the presence of the ligand 6/4-104 at 120 °C to give 6/4-105 (Scheme 6/4.25). The reaction even allows the stereoselective formation of two adjacent quaternary stereogenic centers in high yield. 

Interesting intramolecular cyclization of 1-nitroalkyl radicals generated by one-electron oxidation of aci-nitro anions with CAN is reported. As shown in Eq. 5.44, stereoselective formation of 3,4-functionalized tetrahydrofurans is observed.62 l-Nitro-6-heptenyl radicals generated by one electron oxidation of aci-nitroanions with CAN afford 2,3,4-trisubstituted tetrahydropyrans.63 The requisite nitro compounds are prepared by the Michael addition of 3-buten-l-al to nitroalkenes. 

---